Process of preparing beta-amino-arylethylketone picrates



United States Patent 3,249,606 PROCESS OF PREPARING BETA-AMINO-ARYL-ETHYLKETONE PICRATES Giovanni Pellegrini, Milan, Italy, assignor toMontecatini Societa Generale per lIndustria Mineraria e Chimica, Milan,Italy No Drawing. Filed June 10, 1963, Ser. No. 286,500 Claims priority,application Italy, June 11, 1962, 11,674/ 62 4 Claims. (Cl. 260247.7)

My invention relates to an improved process for the preparation ofbeta-amino-arylethylketone picrates.

Copending applications Serial No. 105,277 and Serial No. 228,757, filedrespectively April 25, 1961 and October 5, 1962, disclose the importanceof beta-aminoarylethylketone picrates for the control of crops againstpathogenic agents belonging to the vegetal kingdom (fungi, bacteria)through preventive sporicidal action by contact or fumigation.

The compounds are of the formula:

wherein A is a simple or substituted aryl group and Y is a simple orsubstituted amino group, sali-fied with picric acid. They have hithertobeen prepared in the two distinct steps of (a) preparing thebeta-amino-arylethylketone hydrochloride by the Mannich synthesis frommethyl-arylketone, hydrochloride of the amine and formaldehyde, and (b)precipitating the picrate by addition of picric acid to thehydrochloride solution. The process, based on two successive reactions,is extremely variable and gives only moderate yields while requiringlarge volumes of solvents and a long series of time-consumingoperations.

Moreover, although it is known that in some particular cases the use ofaqueous solutions of formaldehyde is advisable, the reaction isgenerally promoted by an anhydrous medium and by removal of water ofcondensation during the reaction. Improvements of the Mannich processhave been based on the removal of water by distillation (S. Winstein etal., J. Org. Chem., 11, 218 (1946).

I have found that these beta-amino-arylethylketone picrates may beobtained by direct synthesis, while operating under suitable conditions,with higher yields, in a simpler manner, by reacting a methylarylketone,an amine salt (generally hydrochloride), formaldehyde and picric acid,in a single step.

The obtainment of beta-amino-arylethylketone picrates in this manner issurprising, inasmuch as it was expected that the picric acid would reactquantitatively with the methylarylketone, as occurs when these twosubstances only are allowed to react each other, thereby preventing itfrom reacting with the amine salt and formaldehyde according to theclassical Mannich scheme.

The reaction according to my invention takes place in the presence ofsolvents or mixtures thereof, which are able to display a high solventpower toward the reactant substances and which have, as a characteristicof essential significance, a boiling point not lower than 85 C. underatmospheric pressure. Obviously, when working at pressure higher thanatmospheric, solvents may be employed which under atmospheric pressureshow a boiling point less than the above mentioned value, whereas3,249,606 Patented May 3, 1966 when operating under vacuum solventsemployed may have a higher boiling point at atmospheric pressure. In themethod of my invention, the temperature is of fundamental importance. Aquantitative formation of methylarylketone picrate occurs when operatingat a temperature sufiicient for the picric acid dissolution andparticularly at about C., under the experimental conditions mentioned inthe following examples. In the range between 70 and C., the reactionyields increasing amounts of the beta-amino-arylethylketon-e picratewith increasing temperatures, to give the highest yield at temperaturesgenerally higher than 85 C.

It has been found in particular that hydroalcoholic mixtures may beemployed as the solvents. These mixtures should contain alcohol andwater in such proportions as to keep the reaction mixture at atemperature above 85 C. for the whole reaction time, in order to obtainthe maximum of yields.

The hydroalcoholic mixtures are preferred because alcohol, whichconstitutes already a component of the reaction mixture, is added at theend of the reaction to promote the precipitation of the product; thehydroalcoholic mixtures allow or promote the formation of the aminehydrochloride directly in the synthesis reactor; and they are readilyavailable.

The possibility of operating in aqueous medium is another advantage ofmy process. In fact, according to my process there is no need topreviously prepare the anhydrous amine hydrochloride. On the contrary,the amine hydrochloride may be prepared directly in the synthesisreactor, either by passing gaseous hydrochloric acid into a solution ofthe free amine or by adding aqueous concentrated HCl solution to thereaction solution itself, whereby the preparation process is remarkablysimplified, especially when it is operated on industrial scale. In somecases, yellow small crystals of the final product already begin toseparate during the reaction period, whereas in other cases the liquidremains clear until the end of the reaction. The picrate separation iscarried out by adding to said liquid, at the end of the reaction, asuitable volume of the alcohol employed as the solvent, and by cooling.The crystalline solid product is separated by filtration orcentrifugation.

Reactants are generally employed in the following preferred ratios: onemole amine hydrochloride, one mole methylarylketone, one mole picricacid and two moles and a half of formaldehyde. Under such conditions,the yields are most satisfactory. However, an increase of aminehydrochloride (see Examples 1 and 2) causes an appreciable furtherincrease of yield. Yields have been calculated with reference to theamount of methylketone.

With respect to variation of yield as a function of the reactiontemperature, the results hereinafter reported were achieved through aset of synthesis tests of the betamorpholino ethyl-l-naphthyl ketonepicrate (M. W. 498.44), wherein the temperature was the only variablefactor.

cc. absolute ethyl alcohol, 60 cc. H 0, 2 cc. concentrated HCl, 123.5 g.(1 M) morpholine hydrochloride, 170.2 g. (1 M) l-acetonaphtone, 229.11g. (l M) picric acid, 75 g. (2.5 M) paraformaldehyde are poured in a 2/z-liter, 3-necked flask provided with stirrer, thermometer -and refluxcondenser. It is heated, after agitation has started, at the varioustemperatures indicated hereinbelow, for 2 hours. At the end of thereaction, 600 cc.

alcohol are gradually added while cooling. The product is then filteredand dried.

TABLE I 4 centrated hydrochloric acid, 123. 6 g. (1 M) morpholinehydrochloride, 204.6 g. (1 M) 4-chloro-l-acetor1aphthone, 229.11 g. (1M) picric acid and 75 g. (2.5 M) paraformaldehyde are introduced in a2.5-liter, 3-necked flask pro- 100 cc. absolute ethyl alcohol, 60 cc.water, 2 cc. con- R a M t 5 videdwith stirrer, thermometer and refluxcondenser. e c 10 empem mes Stirring is started and the flask andcontents are heated a under refluxing for 2 hours. The temperature ofthe re- 70 80 90 100 action mixture stabilizes at 91-92" C. After 15-20min- Product g 400 444 440 442 utes the reaction liquid becomes clear.During the reac- M.P.,C 110-120 167-175 182-184 182-184 10 t the ProductSeparates gradually as yellow Crystals Two hours after the reactionmixture reaches the indi- Melting point ofbeta-morpholinoethyl-l-naphthylketone is 186187 O. cated temperature, 1000 CC. ethylalcohol are gradually 1 The reaction temperature of 100 C. has beenattained by operating added- Stlrrlng l5 Continued for about mlnutes,and 3% fiP i inert f fiat fi g t the reaction mixture is then poured ina beaker, allowed (118 O.) gcc1 ir siP we range 8 o 'ace (map mm) mm 815 to cool and filtered to obtain 408 g. beta-morpholino-ethyl- Withregard to the influence of the amounts and ratios 4-chloro-l-n-arhthylketone p1crate, as yellow crystals with of solvents employed, TableII summarizes the results M'P'183 185 C'(y1eld764%) of synthesis testsof beta-morpholino-l-naphthylethyl- Analysis: ketone picrate, performedby repeating the above-men- 2 N theoretical percent, 10.51; foundpercent 10.78 tioned operative conditions and employing the same 0 Cltheoretical percent, 6.65; found percent 6.84 amounts of reactants, butby varying the amount and C theoretical percent, 51.84; found percent51.55 ratios of solvents. H theoretical pencent, 3.97; found percent3.95

TABLE II Ethyl alcohol, cc 600 300 100 100 100 100 100 100 Water, 00..40 50 60 90 The following examples are to illustrate but not to re-Example 3 strict the presentmvennon' 100 cc. absolute ethyl alcohol, 75cc. water, 2 cc. con- Example 1 centrated hydrochloric acid',.123.5 g.(1 M) morpholine hydrochloride 127 g. (l M) acetophenone, 229.11 g. 100cc. absolute ethyl alcohol, 75 cc. water, 2 cc. concentratedhydrochloric acid, 185.4 g. (1.5 M) morpholine (1 M plcnc t and M)parafmtaldehyfi hydrochloride, 204.6 g. (1 M) 4-chloro-l-acetonaphthone,Introduced m 3'necked flask provltieli 229 11 g (1 M) picric acid and 75g (2.5 M) Paraf0rma1 stirrer, thermometer .and reflux condenser. Stirrmg1s dehyde are poured in a 2.5-liter, 3-necked flask provided itarted h i1S p gi g fi i g i with a stirrer, thermometer and reflux condenser.Stirring ig empega f; a s 1i uid becomes is started and the flask andcontents are heated under recon er 5 e .reac Ion eg b t fluxing for 2hours. The inner temperature of the flask clear and after mmutes the prouct egms to Separ-a e stabilizes at 93-94 C. After 15-20 minutes thereaction gradually as yellow pnfstals' Two hours after reactlon liquidbecomes clear. The Product separazes gradually mixture reachestheindicated temperature, 1000 cc. ethyl during the reaction as yellowcrystals. Two hours after 21 2211 8 i a 3g: g g isgi sg li g g g gzi g ggg ggfi g 3 52 g i ggfi fi ggg g ggg ig poured in a beaker,; allowed tocool and then filtered to continued for about 10 minutes the reactionmixture is yleld 379 beta-mp1? holmo ethy1 pi.1enylkqtone Plcrate thenpoured in a beaker and angwed to cool. y filtra as yellow crystals, withM.P. 188-190 C. (yleld 84.6%). tion, 472 g. beta-morpholinoethyl-4-chl0ro-l-naphthyl- Analysis: ketonepicrate is .obtained asyellow crystals having a melt- N theoretical percent, 12.49; foundpercent, 12.60 mg po1nt 182l86 C. -(y1eld 88%). C theoretical percent,50.90; found percent, 51.04 Analysis: H theoretical percent, 4.49; foundpercent, 4.55

8. sites. 221221; a-iaisa passa 92 a C theoretical percent 2 foundercent 51 50 ride 18 first syntheslzed and subsequently precipitatedwlth H theoretical percent 3 Qiound grcent picric acid, a product isobtained having M.P. 187-l93 P C. with an approximate yield of 59%Alternatively, while obtaining identical yields, in lieu of employingpreviously prepared morpholine hydrochlo- Exam! 4 ride, the formationthereof may be achieved, while operating in analogous conditions, bypassing in the flask (con- 100 absolute etilyl l 75 Water 2 containing100 cc. absolute ethyl alcohol 77 cc. water and centrated hydrochlonc122'7 (1 M) dlmethyl' 130.8 g. (1.5 M) morpholine) a stream of anhydrousfi (g a f i gi I g. p1cr1c ac1 an g. para orma e y e ifggf i acld colorchange of Congo are introduced in a 2.5-liter, S-necked flask providedwith In contrast to the above yidd if betwmorpholino stirrer,thermometer and reflux condenser. Stirring isethyl-4-chloro-l-naphthylkentone hydrochloride is first itarted andheatmg under refluJ-u-ng 1S contmued i 2 synthesized and subsequentlyprecipitated with picric acid, i lune; tegperatuffi ablllges at abgut9?: C, a product is obtained Showing M.P. C. with a we ours a ter ereactlon l1qu1 reaches t e indicated ield of about temperature, 1000 cc.ethyl alcohol are gradually added. y Exam le 2 Stirring is continued forabout 10 minutes; the reaction p mixture is then poured in a beaker,allowed to cool, and

filtered to obtain 29.5 g. beta-dimethylamino-ethylphenylketone picrateas yellow crystals with M.P. ISO-151 C. (yield 73.8%).

Analysis:

N theoretical percent, 13.80; found percent, 14.10 C theoreticalpercent, 50.24; found percent, 50.53 H theoretical percent, 4.46; foundpercent, 4.94

When beta-dimethylamino-ethylphenylketone hydrochloride is firstsynthesized and subsequently precipitated with picric acid, the productobtained has a M.P. 150- 152 C. and an approximate yield of 53%.

Example 5 100 cc. absolute ethyl alcohol, 75 cc. water, 2 cc.concentrated hydrochloric acid, 123.5 g. (l M) morpholine hydrochloride,170.2 g. (1 M) l-acetonaphthone, 229.11 g. (1 M) picric acid, 75 g. (2.5M) paraformaldehyde are introduced in a 2.5-liter, 3-necked flask,provided with stirrer, thermometer and reflux condenser. Stirring isstarted and the flask and contents are heated under refluxing for twohours. The inner temperature stabilizes at about 92 C. Two hours afterthe inner liquid reaches the indicated temperature, 1000 cc. ethylalcohol are gradually added. Stirring is continued for about minutes,then the reaction mixture is poured into a beaker, is allowed to cooland filtered to obtain 450 g. beta-morpholino-ethyl-l-naphthylketonepicrate as yellow crystals with a M.P. 180-184 C. (yield 90.2%).

Analysis:

N theoretical percent, 11.24; found percent, 11.49 C theoreticalpercent, 55.42; found percent, 55.24 H theoretical percent, 4.45; foundpercent, 4.67

When first synthesizing beta-morpholinoethyl-l-naphthylketonehydrochloride and subsequently precipitating it with picric acid, theproduct obtained has a M.P. 186 187 C. and an approximate yield of 48%.

Example 6 100 cc. absolute ethyl alcohol, 60 cc. water, 2 cc.concentrated hydrochloric acid, 123.5 g. (1 M) morpholine hydrochloride,170.2 g. (l M) l-acetonaphthone, 229.11 g. (1 M) picric acid, 75 g. (2.5M) formaldehyde are introduced in a 2.5-liter, 3-necked flask providedwith stirrer, thermometer and reflux condenser. Stirring is started andthe flask and contents are heated to maintain, for the whole duration ofreaction (2 hours), the temperature at 100 C. This temperature isobtained by operating at an overpressure of inert gas (nitrogen) of 350mm. Hg. Two hours after the reaction mixture has reached the mentionedtemperature, 600 cc. ethyl alcohol are added while cooling. The productis filtered off and dried to give 442 g.beta-morpholino-l-naphthylketone picrate with a M.P. 182184 C. (yield88.6%).

Analysis:

N theoretical percent, 11.24; found percent 11.40 C theoretical percent,55.42; found percent, 55.08 H theoretical percent, 4.45; found percent,4.47

Example 7 100 cc. absolute ethyl alcohol, 75 cc. water, 2 cc.concentrated hydrochloric acid, 122.7 g. (1 M) dimethylaminehydrochloride, 172 g. (1 M) acetonaphthone, 229.11 g. (1 M) picric acidand 75 g. (2.5 M) paraformaldehyde are introduced in a 2.5-liter,3-necked flask provided with stirrer, thermometer and reflux condenser.Stirring is started and the flask and contents are heated underrefluxing for 2 hours. The inner temperature stabilizes at about 94 C.35 minutes after the reaction begins the liquid becomes clear andremains so till the end. Two hours after the reaction liquid has reachedthe indicated temperature, 1000 cc. ethyl alcohol are gradually added.Stirring is continued for about 10 minutes, the mixture is then pouredin a beaker, allowed to cool and filtered to obtain 385 g.beta-dimethylaminoethyl-l-naphthylketone n6 picrate, as yellow crystalswith a M.P. 170-173 C. (yield 84.4%

Analysis:

N theoretical percent, 12.27; found percent, 12.40 C theoreticalpercent, 54.96; found percent, 55.26 H theoretical percent, 4.41; foundpercent, 4.42

On the contrary, when first synthesizing thebeta-dimethyl-amino-ethyl-naphthylketone hydrochloride and thereafterprecipitating with picric acid, the product obtained shows a M.P.174174.5 C. and an approximate yield of 48%.

Example 8 cc. absolute ethyl alcohol, 75 cc. water, 2 cc. concentratedhydrochloric acid, 122.7 g. (1 M) dimethylamine hydrochloride, 204.6 g.(l M) 4-chloro-acetonaphthone, 229.11 g. (1 M) picric acid and 75 g.(2.5 M) paramormaldehyde are introduced in a 2.5-liter, 3-necked flaskprovided with stirrer, thermometer and reflux condenser. Stirring isstarted and the flask and contents are heated under refluxing for twohours. The inner temperature stabilizes at about 94 C. Two hours afterthe reaction liquid reaches the indicated temperature, 1000 cc. ethylalcohol are gradually added. Stirring is continued for about 10 minutes;thereafter the reaction mixture is poured in a beaker, allowed to cooland filtered to obtain 377 g. beta-dimethylaminoethyl 4 chloro 1naphthylketone picrate as yellow crystals with a M.P. l57 C. (yield76.8%

Analysis:

N theoretical percent, 11.41; found percent, 11.51 Cl theoreticalpercent, 7.22; found percent, 7.13 C theoretical percent, 51.39; foundpercent, 51.85 H theoretical percent, 3.90; found percent, 3.97

On the contrary, when first synthesizing thebetadimethyl-amino-4-chloro-1-naphthylketone hydrochloride andsubsequently precipitating it with picric acid, a product is obtainedshowing a M.P. 157161 C., with an approximate yield of 23%.

Example 9 100 cc. absolute alcohol, 75 cc. Water, 2 cc. concentratedhydrochloric acid, 136 g. (1 M) di-N-propylamine hydrochloride, g. (1 M)l-acetonaphthone, 229.11 g. (1%) picric acid, 75 g. (2.5 M)paraformaldehyde are introduced into a 2.5-liter, 3-necked flask,provided with stirrer, thermometer and reflux condenser. Stirring isstarted under refluxing for two hours. The inner temperature stabilizesat about 94 C. Two hours after the inner liquid has reached theindicated temperature, 1000 cc. ethyl alcohol are gradually added.Stirring is continued for about 10 minutes, the reaction mixture is thenpoured in a beaker, allowed to cool and filtered to obtain 362 g.beta-di-N-propylamine-ethyl-l-naphthylketone picrate as yellow crystalswith a M.P. 132132.5 C. (yield 70.6%

Analysis:

N theoretical percent, 10.93; found percent, 11.02 C theoreticalpercent, 58.60; found percent, 58.58 H theoretical percent, 5.57; foundpert/ant, 5.51

Example 10 125 g. of n-propyl alcohol, 47 cc. of water, lcc. ofconcentrated hydrochloric acid, 61.8 g. (0.5 mol) of morpholinehydrochloride, 125 g. (0.61 mol) of 4-chloro-1-acetonaphthone, 114.55 g.(0.5 mol) of picric acid and 37.5 g.

7 (1.25 mols) of paraformaldehyde are introduced into a 1-liter,3-necked flask provided with an agitator, thermometer and refluxcondenser. Agitation is started and the whole is refluxed for 5 hours(inner temperature 93 C.). After 15-20 minutes, the reaction liquid becomes clear. The product gradually separates during the reaction asyellow crystals. Three hours after the reaction liquid has reached theabove-mentioned temperature, 200 cc. of ethanol are gradually added.Agitation is continued for additional minutes and the reaction mixtureis then poured in a beaker and is left to cool. By filtration, 212 g. ofbeta-morpholinoethyl-4-chlorolnaphthylketone picrate, melting point185-187 C., are obtained (yield with respect to'4-chloro-1-acetonaphthone=65%).

Example 11 125 cc. of n-amyl alcohol, 34 g. of Water, 1 cc. ofconoentrated hydrochloric acid, 61.8 g. (0.5 mol) of morpholinehydrochloride, 125 g. (0.61 mol) of 4-chloro-1- acetonaphthone, 114.55g. (0.5 mol) of picric acid and 37.5 g. (1.25 mols) of paraformaldehydeare placed in a 1-liter, 3'necked flask provided with an agitator, athermometer and a reflux condenser. Agitation is started and thereaction mixture is refluxed for 2 hours (inner temperature 101 C.).After a few minutes, the reaction liquid becomes clear. The productgradually separates during the reaction in the form of yellow crystals.Two hours after the reaction liquid has reached the above tem perature,200 cc. of n-amyl alcohol are gradually added. Agitation is continuedfor 10 additional minutes and the reaction mixture is then poured into abeaker and left to cool. By filtration, 210 g. of beta-morpholino-ethyl-4-chloro-l-naphthylketone picrate, melting point 176- 180 C., areobtained (yield 64.4% with respect to 4- chlorol-acetonaphthone) Iclaim:

1. A process for preparing picrates of beta-aminoarylethylketones, whichcomprises reacting in a single operative step a methylarylketone,formaldehyde, an amine hydrochloride and picric acid, at a temperatureof at least 85 C., in the presence of a solvent.

2. A process for preparing picrates of beta-aminoarylethylketones, whichcomprises reacting in a single operative step a methylarylketone,paraformaldehyde, an amine hydrochloride and picric acid, at atemperature of at least C., in the presence of a solvent.

3. A process for preparing picrates of beta-aminoarylethylketones, whichcomprises reacting in a single operative step a methylarylketone,paraformaldehyde, an amine hydrochloride and picric acid, at atemperature of at least 85 C'., in the presence of a water-alcoholsolvent.

4. A process for preparing picrates of beta-aminoarylehtylketones of theformula R1 AC O-C H2-C Hz-N wherein A is aryl selected from the groupconsisting of simple and substituted phenyl, naphthyl and anthranyl, inwhich the substituents are selected from the group consisting ofhydroxyl, halo, nitro, alkyl and alkoxy, and R and R are each selectedfrom the group consisting of hydrogen, lower alkyl, and together withnitrogen can form a heterocyclic group selected from those consisting ofmorpholino and piperidino, which comprises reacting in a singleoperative step a methylarylketone, paraformaldehyde, an aminehydrochloride and picric acid, at a temperature of at least 85 C., inthe presence of a waterethyl alcohol solvent.

References Cited by the Examiner UNITED STATES PATENTS 3,058,987 10/1962Albrecht et a1. 260570.6

OTHER REFERENCES Harradence et al.: Chem. Abst., vol. 33, col. 5855 and5856 (1939).

Migrdichian, Organic Synthesis, vol. I, pages 157-162 (1957 NollerChemistry of Organic Compounds, 2nd ed., pages 460-461 (1957).

WALTER A. MODANCE, Primary Examiner.

NICHOLAS RIZZO, Examiner.

4. A PROCESS FOR PREPARING PICRATES OF BETA-AMINOARYLEHTYLKETONES OF THEFORMULA